Uremic symptoms can be limited by reducing dietary protein and/or giving supplements of amino acids or their nitrogen-free ketoanalogues, but only if protein nutrition is maintained. Because this therapy has been shown to slow the progression of renal insufficiency in patients with chronic renal failure, it will be used more frequently even though low protein diets may increase the risk of malnutrition in uremic patients. This proposal is directed at determining how the balance between protein synthesis (PS) and degradation (PD) is altered in experimental uremia in order to provide a rational basis for regimens designed to maintain protein nutrition. We have found that abnormalities in muscle glucose metabolism are closely related to net PD in normal rats and rats with acute uremia and other catabolic conditions. Therefore, improving insulin-mediated glucose metabolism might decrease muscle PD. We also found that alpha-ketoisocaproate and its metabolites decrease PD in muscles of normal and uremic rats, providing a rationale for its use in treating uremic subjects. We propose to use incubated tissues and the perfused hindquarter of rats to examine the following questions: 1) How do uremia and metabolic acidosis affect the insulin responsiveness of PS and PD and of glucose metabolism? 2) How are abnormalities in protein turnover and glucose metabolism related in uremia? 3) How will exercise training, which improves insulin-mediated muscle glucose metabolism in normal rats, affect PS and PD and glucose metabolism in uremic rats? 4) How does uremia affect the metabolism of branched-chain amino acids (BCAA)? 5) Can the composition of the diet be changed to improve protein nutrition and correct abnormalities in BCAA metabolism? These experiments should provide insight into the causes of increased protein catabolism in uremia and will provide a more rational basis for improving the nutritional therapy of patients with acute and chronic renal failure.